Phenamacril is a reversible and noncompetitive inhibitor of Fusarium class I myosin

Abstract

Edited by Velia M. FowlerThe cyanoacrylate compound phenamacril (also known as JS399 -19) is a recently identified fungicide that exerts its antifungal effect on susceptible Fusarium species by inhibiting the ATPase activity of their myosin class I motor domains. Although much is known about the antifungal spectrum of phenamacril, the exact mechanism behind the phenamacril-mediated inhibition remains to be resolved. Here, we describe the characterization of the effect of phenamacril on purified myosin motor constructs from the model plant pathogen and phenamacril-susceptible species Fusarium graminearum, phenamacril-resistant Fusarium species, and the mycetozoan model organism Dictyostelium discoideum. Our results show that phenamacril potently (IC 50 ϳ360 nM), reversibly, and noncompetitively inhibits ATP turnover, actin binding during ATP turnover, and motor activity of F. graminearum myosin-1. Phenamacril also inhibits the ATPase activity of Fusarium avenaceum myosin-1 but has little or no inhibitory effect on the motor activity of Fusarium solani myosin-1, human myosin-1c, and D. discoideum myosin isoforms 1B, 1E, and 2. Our findings indicate that phenamacril is a species-specific, noncompetitive inhibitor of class I myosin in susceptible Fusarium sp.

Structural basis of Fusarium myosin I inhibition by phenamacril

“…These compounds have been developed to inhibit mammalian myosins. In contrast, phenamacril is the only reported inhibitor that is specific for some plant pathogens [4,27,28].…”

“…Phenamacril is a novel reversible and non-competitive inhibitor of Fusarium myosin I [27]. All Fusarium species have only a single class I myosin.…”

“…Phenamacril functions as a potent fungicide against selective Fusarium spp. such as F. graminearum, F. asiaticum, and F. fujikuroi [27,29], as well as human pathogenic strains of F. oxysporum [30], but has low or no activity against other Fusarium spp., other fungi, myosins 1B, 1E, or 2 from Dictyostelium or mammalian Myo1c [27,28]. Phenamacril shows excellent activity in the field and has been extensively used to control Fusarium head blight (FHB) and rice bakanae disease in China [30][31][32].…”

The b‐ZIP transcription factor FgTfmI is required for the fungicide phenamacril tolerance and pathogenecity in Fusarium graminearum

“…Previous studies revealed that the class I myosin, FgMyoI is the drug target of phenamacril in F. graminearum . Phenamacril directly binds with FgMyo1 and suppresses the ATPase activity of FgMyo1 . In the laboratory, substitution of an amino acid residue in FgMyo1 or its homologs in F. asiaticum and F. fujikuroi leads to high resistance to the fungicide .…”

“…26,27 Phenamacril directly binds with FgMyo1 and suppresses the ATPase activity of FgMyo1. 26,28 In the laboratory, substitution of an amino acid residue in FgMyo1 or its homologs in F. asiaticum and F. fujikuroi leads to high resistance to the fungicide. 25,26 Until now, phenamacril resistant strains of F. graminearum have not been found in the field, while resistant strains of F. fujikuroi have existed in the field for some time.…”